Oxycodone is a semi-synthetic, μ-opioid receptor specific ligand with clear agonist properties.1 In man, oxycodone may produce any of a variety of effects including analgesia. Parenteral oxycodone was used mainly for the treatment of acute postoperative pain whereas combinations, for example oxycodone and acetaminophen, were used for moderate pain. 1 E. Kalso, Journal of Pain and Symptom Management, Volume 29, Issue, Supplement 1, May 2005, 47-56
Examples of immediate release (IR) products containing oxycodone include Percocet®, Percodan®, Roxocet®, and generic equivalents thereof. Examples of sustained-release (SR) dosage forms include Oxycontin® and generic equivalents thereof.
Oxycodone is most commonly derived from thebaine, a minor alkaloid in the papaver somniferum poppy, and from thebaine analogues prepared from codeinone 14-Hydroxycodeinone is the immediate precursor to oxycodone in these syntheses.
Thebaine can be obtained from extraction from the poppy plant papaver somniferum. However, since morphine is the major alkaloid, which accumulates in the capsules of the papaver somniferum plant, the supply of thebaine from this source is limited to some fraction of the demand for morphine. The major source of natural thebaine currently is the concentrated poppy straw (CPS) from a stably reproducing papaver somniferum plant which has been exposed to a mutagenizing agent such that the straw contains thebaine and oripavine constituting about 50% by weight or greater of the alkaloid combination consisting of morphine, codeine, thebaine and oripavine2. 2 A. J Fist, C. J. Byrne and W. L. Gerlach, US 2004/0197428 and U.S. Pat. Nos. 6,723,894, 6,376,221, and 6,067,749
Thebaine has also been prepared by total synthesis routes, which are difficult and expensive3. Thebaine has also been prepared by the methylation of codeinone in the presence of strong base4,5 and oxidation of codeine methylether6. 3 U.S. Pat. No. 4,613,668 and U.S. Pat. No. 4,795,8134 A. Coop and K. Rice, Heterocycles, 49, 1998, 43-47.5 B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No. 6,365,742 B16 R. Barber and H. Rapaport, U.S. Pat. No. 4,045,440
Purified thebaine is normally used for conversion to oxycodone but the use of thebaine CPS directly for the manufacture of oxycodone has also been disclosed7,8. 7 See claims 9 and 10 of A. J. Fist, C. J. Byrne & W. L. Gerlach, U.S. Pat. No. 6,376,221 B18 C. A. Francis, Z. Lin, C. A. Kaldahl, K. G. Antczak, V. Kumar, U.S. Pat. No. 7,071,336
Oxidation of the thebaine may alternatively be performed using potassium dichromate in acetic acid9, performic acid10, hydrogen peroxide in acetic acid9 or peracetic acid11. Improved yield, however, has been reported to be obtained by oxidizing with m-chloroperbenzoic acid in acetic acid-trifluoroacetic acid mixture12. 9 Freund et al, J. Prakt. Chem., 94, 135, (1916).10 Krassnig, Hederer, Schmidhammer, Arch. Pharm. Med. Chem., 1996, 32511 Snuperak et al., WO 2006/019364 A112 Hauser et al., J. Med. Chem., 17, 1117 (1974) and Schwartz, U.S. Pat. No. 4,795,813
14-Hydroxymorphinans have also been prepared from thebaine analogues derived from codeine without a thebaine intermediate13. 14-Hydroxycodeinone, the precursor to oxycodone, has been prepared from codeinone dienol acetate14 the ethyl dienol ether and the tert-butyl dimethylsilyl dienol ether of codeinone5. 13 Schwarz & Schwartz, U.S. Pat. No. 4,472,253 and N D Wallace, J. Med. Chem., 24, 1525-1528, 1981.14 B-S. Huang, Y. Lu, B-Y. Ji, A. S. Christodoulou U.S. Pat. No. 6,008,3555 B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No. 6,365,742 B1
The most common method for the conversion of 14-hydroxycodeinone to oxycodone is catalytic hydrogenation using a noble metal catalyst, preferably palladium, and hydrogen gas9. Reduction of 14-hydroxycodeinone to oxycodone has also been performed using diphenylsilane and Pd(Ph3P)/ZnCl2 or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid.15 Oxycodone may be prepared from thebaine by: dissolution of thebaine in aqueous formic acid, oxidation treatment with 30% hydrogen peroxide16, neutralization with aqueous ammonia to yield 14-hydroxycodeinone and hydrogenation of the 14-hydroxycodeinone in acetic acid with the aid of a palladium-charcoal catalyst.17 9 Freund et al, J. Prakt. Chem., 94, 135, (1916).15 F-T Chiu, Y. S. Lo U.S. Pat. No. 6,177,56716 Seki, Chem. Pharm. Bull. 18, 671-676 (1970).17 Remington's Pharmaceutical Sciences, 1041, (1975).
Oxycodone has also been prepared from thebaine bitartrate and codeinone ethyldienol ether by oxidation with hydrogen peroxide in formic acid and isopropanol, followed by catalytic hydrogenation5. Oxycodone has also been prepared by the oxidation with peracetic acid of codeinone dienol silylether in organic solvents to give 14-hydroxycodeinone, followed by catalytic hydrogenation in acetic acid solution15. 5 B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No. 6,365,742 B115 F-T Chiu, Y. S. Lo U.S. Pat. No. 6,177,567
During the oxidation of thebaine to give 14-hydroxycodeinone, several by-products are formed. In particular, 7,8-dihydro-8,14-dihydroxycodeinone (DHDHC) is formed by acid catalyzed aqueous hydrolysis of 14-hydroxycodeinone as shown in Scheme 1.
                Reaction scheme of the process used to produce oxycodone from thebaine        
It was previously noted that DHDHC is easily converted to 14-hydroxycodeinone18. This conversion occurs during the conversion of oxycodone base to oxycodone hydrochloride, thus 14-hydroxycodeinone is present in the final oxycodone hydrochloride. Oxycodone hydrochloride is available from a number of suppliers including Noramco Inc., and Mallinckrodt. Current commercially available oxycodone hydrochloride API and oxycodone hydrochloride prepared by known procedures have levels of 14-hydroxycodeinone of greater than 100 ppm. 18 Weiss. J. Org. Chem., 22, 1505, (1957)
Recent ICH guidelines suggest that there is a requirement for an oxycodone hydrochloride composition containing reduced amounts of 14-hydroxycodeinone relative to current commercially available oxycodone hydrochloride.
14-Hydroxycodeinone belongs to a class of compounds known as α,β-unsaturated ketones. The class of compounds known as α,β-unsaturated ketones have been designated as potential gene-toxins19 due to their susceptibility to the Michael addition reaction (addition of nucleophiles to the 1(β) position of an α,β-unsaturated ketone)20. 19 “Genotoxic impurities in Pharmaceuticals”, accepted for publication in Regulatory Toxicology and Pharmacology, Dec. 5, 2005.20 March's Advanced Organic Chemistry, Jerry March and Michael B Smith, John Wiley & Sons 2001, pages 1022-1024
A recent patent application assigned to Euro-Celtique discloses reducing the levels of 14-hydroxycodeinone in oxycodone hydrochloride by re-submitting the product to conditions similar to those of the original hydrogenation21. In addition to reduction by hydrogenation, the α,β-double bond adjacent to the carbonyl function can be reduced by other means such as transfer hydrogenation (using formic acid, isopropyl alcohol, cyclohexene, indoline, sodium borohydride, tetrahydroquinoline, 2,5-dihydrofuran, phosphoric acid or combinations thereof) and reduction by sodium hydrosulphite22. Dissolving metal reductions (zinc or magnesium[Clemmenson reduction]) convert 14-hydroxycodeinone to a number of products including mainly dihydrohydroxythebainone23. In addition, the potential gene-toxin activity of α,β-unsaturated ketones can be mitigated by subjecting them to the type of reaction (Michael addition) which makes them potential gene-toxins in the first place. One of the most potent nucleophiles in biological systems is the thiol group (—SH), which is present in the amino acid cysteine, which in turn is common in proteins and often critical to protein folding and therefore its biological activity. Cysteine has been shown to react with α,β-unsaturated ketones at the 1(β) position of the double bond, thereby saturating the double and rendering it incapable to accept further nucleophiles at this position and therefore no longer gene-toxic24 21 R. Chapman, L. S. Rider, Q. Hong, D. Kyle & R. Kupper, US 2005/0222188 A1.22 M. Freund, E. Speyer, U.S. Pat. No. 1,479,293.23 R. E. Lutz, L. Small, J. Org. Chem. 4, 220 (1939). See also Banerjee, A. K.; Alvarez, J.; Santana, M.; Carrasco, M. C. Tetrahedron, 1986, 42, 6615.24 See Cysteine conjugate of morphinone: Nagamatsu, Kunisuke; Kido, Yasumasa; Terao, Tadao; Ishida, Takashi; Toki, Satoshi; Drug Metabolism and Disposition (1983), 11(3), 190-4
14-hydroxycodeinone may also be formed during the conversion of oxycodone base to oxycodone hydrochloride due to the conversion of DHDHC to 14-hydroxycodeinone by dehydration (see Scheme 1). The Euro-Celtique patent teaches that this conversion is promoted by excess hydrochloric acid and the 25 resulting 14-hydroxycodeinone is converted to oxycodone hydrochloride by catalytic hydrogenation21. 21 R. Chapman, L. S. Rider, Q. Hong, D. Kyle & R. Kupper, US 2005/0222188 A1.